1. Field of the Invention
The present invention relates to compositions and methods of treatment for Parkinson's Disease, by administration to a subject suffering or susceptible to same, of a diarylmethylpiperazine compound that exhibits delta opioid receptor agonist and/or mu opioid receptor antagonist activity and optionally in combination with other active Parkinson treating agents.
2. Description of the Related Art
Parkinson's disease is a degenerative disorder identified by the loss of motor control progressing to loss of motor functions as well as Parkinsonian dementia in many cases. The pathophysiology of the disease is dominated by a loss of dopamine containing neurons in the brain, particularly in the basal ganglia areas.
Current medical therapy for Parkinson's disease is based primarily around the replacement of the dopamine deficit through the administration of L-DOPA with or without dopamine agonists. However, after 3-5 years of L-DOPA treatment alone patients develop motor fluctuations due to “wearing-off” of the therapeutic effect, “on-off” fluctuations in efficacy immediately after dosing, or most commonly, an “overshoot” of effect manifested as abnormal involuntary movements (AIMs; dyskinesias) (Hill et al., 2000; Silverdale et al., 2003). The co-administration of dopamine agonists (primarily ergot-derived) with L-DOPA slows the development of these side-effects but does not prevent their eventual onset (Hill et al., 2000; Silverdale et al., 2003). Critically, once patients have experienced L-DOPA-induced dyskinesias they are “primed” for dyskinesias in response to any currently available dopamine-based therapeutic (Hill et al., 2000). In light of these debilitating side-effects and the loss of efficacy over extended L-DOPA use, non-dopaminergic therapy for Parkinson's disease would be highly desirable, whether as a monotherapy or as an adjunct therapy to low-dose L-DOPA administration. One such target is the opioid receptor system, and the delta receptor subtype in particular (Hille et al, 2001).
While the role of the opioid peptides in the pathophysiology of Parkinson's disease is poorly understood compared to that of dopamine, the distribution of opioid peptides and receptor expression throughout the basal ganglia has prompted considerable investigation (Hille et al. 2001). The co-localization of met- and leu-enkephalin with GABA in striatal neurons projecting to the external globus pallidus (GPe) is well established (Cuello, et al. 1978; Gerfen, et al., 1988), while met-enkephalin has been shown to decrease depolarization-evoked GABA release from rat globus pallidus, an effect considered to be anti-parkinsonian in nature (Maneuf et al., 1994). In addition, met-enkephalin has been shown to be elevated in the striatum of parkinsonian rodent and primate models as well as in Parkinson's disease patients (Nisbet et al., 1995; Maneuf et al., 1994; De Ceballos et al., 1993). Furthermore, drug-induced dyskinesias in rodents, primates and Parkinson's disease patients have been shown to be associated with elevated levels of striatal preproenkephalin B (Nisbet et al., 1995; Herrero et al., 1995; Jolkkonen et al., 1995; Henry et al., 1996). With the identification of met-enkephalin as one of the primary endogenous ligand for the delta receptor, the anti-parkinson potential of delta receptor activation becomes clear.
Some anti-parkinsonian effect has been demonstrated for delta receptor activation by rodent and primate studies with the delta receptor-selective agonist, SNC80 (Hille et al, 2001). SNC80 is a highly selective delta receptor agonist and is an analogue of benzhydrylpiperazines such as BW373U86 (Chang et al., 1993). SNC80 at 10 mg/kg i.p. restored behavioral deficits observed in rats treated with reserpine or dopamine receptor antagonists (haloperidol or SCH23390) including ambulatory behavior, grooming, rearing, social interaction and exploration, and static investigation. When administered at similar dose levels to MPTP-treated marmosets, SNC80 restored motor activity, bradykinesia and disability scores to normal. The parkinsonian posture induced by MPTP treatment in this model was not statistically reversed by SNC80 although substantial improvements were observed in some individual animals (Hille et al., 2001).
These reports, in both rodent and non-human primate models of Parkinson's disease, indicate that the delta opioid receptor agonist SNC80 has a powerful anti-parkinsonian effect. Interestingly, even at relatively high doses behavior returned to normal levels but did not show the hyperkinesias associated with supra-optimal doses of L-DOPA (Hille et al, 2001). The mechanism of action appears to be via the delta receptor (Hille et al, 2001). However, SNC80 is neither orally active nor particularly safe for use in a clinical setting. SNC80 has been shown to produce seizure-like convulsions in mice and rats, and as such cannot be pursued for clinical study (Broom, et al., 2002).
A highly selective mu antagonist cyprodime was shown to reduce completely L-DOPA-induced dyskinesia in the MPTP-lesioned primate (marmosets) model of Parkinson's disease without attenuation of the anti-parkinsonian actions of L-DOPA (Henry et al., 2001). It appears that the highly selective mu antagonist cyprodime was more effective than less selective antagonists such as naltrexone and naltrindole at the dose of 10 mg/kg i.p. This data plus the demonstrated increase in the synthesis of proenkephalin A and B in basal ganglia in the animal model of L-DOPA-induced dyskinesia and in postmortem tissue from Parkinson's disease patients treated with conventional therapy (Nisbet et al., 1995; Maneuf et al., 1994; De Ceballos et al., 1993) provides strong evidence that mu-receptor activation may contribute to the development of dyskinesia in Parkinson's disease patients after chronic L-DOPA based therapy.
Thus, there is a need for an effective opioid-based treatment for Parkinson's disease that not only acts as a delta opioid receptor agonist but also optionally exhibits mu opioid receptor antagonist activity while negating the unwanted side effects of known opioid compositions currently used in the treatment of Parkinson's disease.